Rectal gel with date palm phenolics and vanillic acid

ABSTRACT

A gel composition for treating bowel diseases comprising about 0.1 to about 2.5 wt. % of an anti-epileptic agent; about 0.8 to about 2.0% wt. % of a collagen complexed with a date palm extract of Khalas cultivar and carboxymethylcellulose; about 10 to about 50 μg/mL of vanillic acid; about 0.1 to about 0.3 μg of stearic acid; and water; wherein all wt. % are based on g/100 g of the gel composition. This gel composition can be topically administered to the rectum of a patient to treat one or more bowel diseases, disorders, or conditions.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.18/113,721, filed on Feb. 24, 2023.

BACKGROUND 1. Field

The disclosure of the present patent application relates to a gelcomposition for treating bowel diseases.

2. Description of the Related Art

Patients diagnosed with various forms of bowel irritation, worldwide,have drastically increased over the last decade. These chronicconditions can result in significant morbidity for individuals includinglong hospitalizations, prolonged exposure to antibiotics, acute andchronic pain, the need for cumbersome wound care, and restrictedmobility. Despite the enormous impact of these chronic wounds on bothindividuals and society, effective therapies are lacking. Thus, themodification, correction, or prevention of such bowel irritation hasfar-reaching consequences, both on patient outcomes and on healthcareexpenditures.

For example, inflammatory bowel disease (IBD), specifically ulcerativecolitis, is characterized by intestinal inflammation, oxidative stress,and a disrupted mucosal barrier. Because current treatments are largelyinefficient to improve symptoms and survival of patients suffering fromIBD, such as ulcerative colitis, alternative therapies are urgentlyneeded.

One product being studied for its use in wound healing is collagen,which may promote healing by restoring or preventing the breakdown ofthe skin or tissue/organ extracellular matrix. Collagen is abiodegradable protein and exists in a form of fibers in connectivetissue of most animals. The primary function of collagen is to maintainthe integrity of tissues and to provide tensile strength essential totissues. At present, more than 21 different types of collagen have beendiscovered.

Collagen can be manufactured in different forms, such as sponge, gel,tube, or sheet. A porous collagen matrix can facilitate cell migration,cell growth or encapsulation and release of drugs. Processes for thepreparation of a collagen matrix typically include comminuting startingmaterials generally by slicing or grinding, extraction, purification,lyophilization, and further comprising a cross-linking process. Acidicor alkaline collagens are generally used and cross-linked by adehydrothermal process or by some chemical cross-linking agents andlyophilized to obtain porous collagen matrices.

Further, although there are numerous products for bowel irritation onthe market, many consumers are hesitant to use chemically synthesizedproducts perceived as being environmentally unfriendly or otherwiseunsafe. Consequently, there is a need for such products that areeffective and have natural components. Thus, a bowel treatingcomposition solving the aforementioned problems is desired.

SUMMARY

The present subject matter relates to a gel composition for treatingbowel diseases in a patient.

In one embodiment, the present subject matter relates to a gelcomposition comprising: about 0.1 to about 2.5 wt. % of ananti-epileptic agent; about 0.8 to about 2.0% wt. % of a collagencomplexed with a date palm extract of Khalas cultivar andcarboxymethylcellulose; about 10 to about 50 μg/mL of vanillic acid;about 0.1 to about 0.3 μg of stearic acid; and water; wherein all wt. %are based on g/100 g of the gel composition.

In another embodiment, the present subject matter relates to a methodfor treating a bowel disease, disorder, or condition in a patient inneed thereof, the method comprising: topically administering atherapeutically effective amount of the gel composition as describedherein to a rectum of the patient.

The present subject matter also relates to the use of a gel compositionas described herein in the manufacture of a medicament for treating abowel disease, disorder, or condition in a patient.

The present subject matter further relates to a pharmaceuticalformulation comprising the gel composition as described herein fortreating, reducing the risk of, preventing, or alleviating a symptom ofa bowel disease, disorder, or condition in a patient.

In some embodiments of the present subject matter, the gel compositionis administered topically, intradermally, or intramuscularly to thepatient. In some embodiments, the gel composition is administeredrectally to the patient. In some embodiment, the gel composition isadministered to the patient a plurality of times. In some examples, thecomposition is administered rectally to the patient. In some embodiment,the gel is administered daily to the patient.

This Summary is neither intended nor should it be construed as beingrepresentative of the full extent and scope of the present disclosure.Moreover, references made herein to “the present disclosure,” or aspectsthereof, should be understood to mean certain embodiments of the presentdisclosure and should not necessarily be construed as limiting allembodiments to a particular description. The present disclosure is setforth in various levels of detail in this Summary as well as in theattached drawings and the Detailed Description and no limitation as tothe scope of the present disclosure is intended by either the inclusionor non-inclusion of elements, components, etc. in this Summary.

These and other features of the present subject matter will becomereadily apparent upon further review of the following specification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a chart various dosages of different compositions based onpatient body weight.

FIG. 2 is a series of micrographs showing histopathological examinationof inflammation in the bowels using different compositions.

FIG. 3 is a chart showing histopathological scores for inflammation andinfiltration in the bowels using different compositions.

FIG. 4 is a chart showing gene expression of certain inflammatorymarkers in the bowels following treatment with different compositions.

FIG. 5 is a chart showing cytokine estimation in colon tissues followingtreatment with different compositions.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following definitions are provided for the purpose of understandingthe present subject matter and for construing the appended patentclaims.

It should be understood that the drawings described above or below arefor illustration purposes only. The drawings are not necessarily toscale, with emphasis generally being placed upon illustrating theprinciples of the present teachings. The drawings are not intended tolimit the scope of the present teachings in any way.

Throughout the application, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present teachings can alsoconsist essentially of, or consist of, the recited components, and thatthe processes of the present teachings can also consist essentially of,or consist of, the recited process steps.

It is noted that, as used in this specification and the appended claims,the singular forms “a”, “an”, and “the” include plural references unlessthe context clearly dictates otherwise.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components, or the element or component can beselected from a group consisting of two or more of the recited elementsor components. Further, it should be understood that elements and/orfeatures of a composition or a method described herein can be combinedin a variety of ways without departing from the spirit and scope of thepresent teachings, whether explicit or implicit herein.

The use of the terms “include,” “includes”, “including,” “have,” “has,”or “having” should be generally understood as open-ended andnon-limiting unless specifically stated otherwise.

The use of the singular herein includes the plural (and vice versa)unless specifically stated otherwise. In addition, where the use of theterm “about” is before a quantitative value, the present teachings alsoinclude the specific quantitative value itself, unless specificallystated otherwise. As used herein, the term “about” refers to a ±10%variation from the nominal value unless otherwise indicated or inferred.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which the presently described subject matter pertains.

Where a range of values is provided, for example, concentration ranges,percentage ranges, or ratio ranges, it is understood that eachintervening value, to the tenth of the unit of the lower limit, unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the described subject matter. Theupper and lower limits of these smaller ranges may independently beincluded in the smaller ranges, and such embodiments are alsoencompassed within the described subject matter, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the described subject matter.

Throughout the application, descriptions of various embodiments use“comprising” language. However, it will be understood by one of skill inthe art, that in some specific instances, an embodiment canalternatively be described using the language “consisting essentiallyof” or “consisting of”.

A “subject” herein is typically a human. In certain embodiments, asubject is a non-human mammal. Exemplary non-human mammals includelaboratory, domestic, pet, sport, and stock animals, e.g., mice, cats,dogs, horses, and cows. Typically, the subject is eligible fortreatment, e.g., treatment of a gastrointestinal inflammatory disorder.As used herein, the term “patient” refers to any single subject forwhich treatment is desired. In certain embodiments, the patient hereinis a human. A subject can be considered to be in need of treatment.

As used herein, “gastrointestinal inflammatory disorders” or “boweldiseases, disorders, or conditions” are a group of chronic disordersthat cause inflammation and/or ulceration in the mucous membrane. Thesedisorders include, for example, inflammatory bowel disease (e.g.,Crohn's disease, ulcerative colitis, indeterminate colitis andinfectious colitis), mucositis (e.g., oral mucositis, gastrointestinalmucositis, nasal mucositis and proctitis), necrotizing enterocolitis andesophagitis Inflammatory Bowel Disease (IBD) is used interchangeablyherein to refer to diseases of the bowel that cause inflammation and/orulceration and includes without limitation Crohn's disease andulcerative colitis. Crohn's disease (CD) and ulcerative colitis (UC) arechronic inflammatory bowel diseases of unknown etiology. Crohn'sdisease, unlike ulcerative colitis, can affect any part of the bowel.The most prominent feature of Crohn's disease is the granular,reddish-purple edematous thickening of the bowel wall. With thedevelopment of inflammation, these granulomas often lose theircircumscribed borders and integrate with the surrounding tissue.Diarrhea and obstruction of the bowel are the predominant clinicalfeatures. As with ulcerative colitis, the course of Crohn's disease maybe continuous or relapsing, mild or severe, but unlike ulcerativecolitis, Crohn's disease is not curable by resection of the involvedsegment of bowel. Most patients with Crohn's disease require surgery atsome point, but subsequent relapse is common and continuous medicaltreatment is usual.

Crohn's disease may involve any part of the alimentary tract from themouth to the anus, although typically it appears in the ileocolic,small-intestinal or colonic-anorectal regions. Histopathologically, thedisease manifests by discontinuous granulomatomas, crypt abscesses,fissures and aphthous ulcers. The inflammatory infiltrate is mixed,consisting of lymphocytes (both T and B cells), plasma cells,macrophages, and neutrophils. There is a disproportionate increase inIgM- and IgG-secreting plasma cells, macrophages and neutrophils.

Ulcerative colitis (UC) afflicts the large intestine. The course of thedisease may be continuous or relapsing, mild or severe. The earliestlesion is an inflammatory infiltration with abscess formation at thebase of the crypts of Lieberkuhn. Coalescence of these distended andruptured crypts tends to separate the overlying mucosa from its bloodsupply, leading to ulceration. Symptoms of the disease include cramping,lower abdominal pain, rectal bleeding, and frequent, loose dischargesconsisting mainly of blood, pus, and mucus with scanty fecal particles.A total colectomy may be required for acute, severe or chronic,unremitting ulcerative colitis. The clinical features of UC are highlyvariable, and the onset may be insidious or abrupt, and may includediarrhea, tenesmus and relapsing rectal bleeding. With fulminantinvolvement of the entire colon, toxic megacolon, a life-threateningemergency, may occur. Extraintestinal manifestations include arthritis,pyoderma gangrenoum, uveitis, and erythema nodosum.

An “effective amount” of a gel composition as described herein is anamount sufficient to carry out a specifically stated purpose. An“effective amount” may be determined empirically and in a routinemanner, in relation to the stated purpose. The term “therapeuticallyeffective amount” refers to an amount of a gel composition as describedherein to “treat” a disease or disorder in a subject.

As used herein, “suppressing”, “suppress”, or “suppression” meansstopping the inflammation from occurring, worsening, persisting,lasting, or recurring.

“Reducing”, “reduce”, or “reduction” means decreasing the severity,frequency, or length of one or more symptoms of a disease, disorder, orcondition as described herein.

“Treating” or “treatment” or “alleviation” refers to both therapeutictreatment and prophylactic or preventative measures, wherein the objectis to prevent or slow down (lessen) the targeted pathologic disease,condition, or disorder. Those in need of treatment include those alreadywith the disease, condition, or disorder as well as those prone to havethe disease, condition, or disorder or those in whom the disease,condition, or disorder is to be prevented. A subject or mammal issuccessfully “treated” for a disease, condition, or disorder if, afterreceiving a therapeutic amount of a gel composition as described herein,the subject shows observable and/or measurable reduction in, or absenceof, one or more symptoms of the disease, condition, or disorder.Reduction of these signs or symptoms may also be felt by the patient.

For purposes of better understanding the present teachings and in no waylimiting the scope of the teachings, unless otherwise indicated, allnumbers expressing quantities, percentages or proportions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about”.Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, each numerical parametershould at least be construed in light of the number of reportedsignificant digits and by applying ordinary rounding techniques.

The present subject matter is directed to a gel composition for treatingbowel diseases in a patient. In one embodiment, the present subjectmatter relates to a gel composition comprising: about 0.1 to about 2.5wt. % of an anti-epileptic agent; about 0.8 to about 2.0% wt. % of acollagen complexed with a date palm extract of Khalas cultivar andcarboxymethylcellulose; about 10 to about 50 μg/mL of vanillic acid;about 0.1 to about 0.3 μg of stearic acid; and water; wherein all wt. %are based on g/100 g of the gel composition.

In certain embodiments, the gel composition can further comprise one ormore components selected from the group consisting of chitosan, timogen,propylene glycol, Carbopol, EDTA, and sodium hydroxide. In this regard,0.01-1.0 mM sodium hydroxide can increase the gelling rheology. Thetimogen and chitosan can improve the absorption of active moieties inthe gel and lead to decreased disease symptoms and treatment period.

In an embodiment, the collagen used in the present gel compositionscontains one or more collagen enzymatic hydrolysates. By way ofnon-limiting example, the collagen used in the present gel compositionsis pepsin treated collagen I, which can undergo gelatinization followedby enzymatic hydrolysis. The collagen used can be obtained fromconnective tissue of any suitable animal, e.g., cow, pig, sheep,chicken, duck, turkey, goose, whale, or shark. The connective tissue caninclude skin, dermis, subcutaneous tissue, ligament, tendon,aponeurosis, cartilage, bone tissue, cornea, sclera, aorta, vessel, andthe like.

In certain embodiments, the collagen used in the present gelcompositions can be made by heating a collagen hydrolysates solution,adjusting the pH of the solution, and adding papain to performenzymolysis to obtain an enzymolysis reaction solution. In this regard,collagen undergoing this process and being used in the present gelcompositions can be dosed in an amount of about 5 to about 15 mg/kg bodyweight of the patient, or about 5 mg/kg, about 6 mg/kg, about 7 mg/kg,about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, or any range ofany two endpoints thereof, by body weight of the patient. Further suchcollagen can include about 25 to about 80 mg/kg body weight of thepatient, of collagen enzymatic hydrolysates, or about 25 mg/kg, aboutmg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg,about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75mg/kg, about 80 mg/kg, or any range of any two endpoints thereof, bybody weight of the patient, of collagen enzymatic hydrolysates.

In another embodiment, the date palm extract used in the presentcompositions is an extract of the Khalas cultivar date palm. Thevanillic acid is one phenolic component of the date palm extract fromthe Khalas cultivar date palm. As the concentration of vanillic acid inthe date palm extract is less than other phenolic components of the datepalm extract, it may be necessary to add vanillic acid obtained from anoutside source to provide an effective amount of vanillic acid. Incertain embodiments, an effective amount of vanillic acid in the presentcomposition is about 10 μg/mL to about 50 μg/mL of vanillic acid, orabout 10 μg/mL, about μg/mL, about 20 μg/mL, about 25 μg/mL, about 30μg/mL, about 35 μg/mL, about 40 μg/mL, about 45 μg/mL, about 50 μg/mL,or any range of any two endpoints thereof, of vanillic acid. The datepalm extract may contain other phenolic components, by way ofnon-limiting example including gallic acid, p-coumaric acid, caffeicacid, vanillic acid and syringic acid. In certain embodiments, it isanticipated the presence of the vanillic acid in the designated amountsin the present gel compositions will contribute to enhancing healingproperties of the gel compositions.

The total phenolic content of the date palm extract used can bedetermined by a modified Folin-Ciocalteu method, wherein 1 mg of thedate palm extract is suspended in 1 ml water, with 100 μl ofFolin—Ciocalteu reagent being added to the mixture after 1 minute.Subsequently, the mixture is incubated in a shaking incubator at 40° C.for 30 min and its absorbance measured at 760 nm. Gallic acid can beused as a standard for the calibration curve. The phenolic content canbe expressed as gallic acid equivalents by using the following linearequation: y=0.921x+0.0227, R²=0.9771, where y is the absorbance and x isthe concentration as gallic acid equivalents (mg/ml). Following thisprocedure, the estimated quantity of total phenolic content in the datepalm extract was 22.86 mg gallic acid equivalents/g of dry date palmextract. Accordingly, the present gel compositions can contain about 20to about 25 mg of total phenolics per g of dry date palm extract, orabout 20 mg, about 20.5 mg, about 21 mg, about 21.5 mg, about 22 mg,about 22.5 mg, about 23 mg, about 23.5 mg, about 24 mg, about 24.5 mg,about 25 mg, or any range of any two endpoints thereof, of totalphenolics per g of dry date palm extract.

The present compositions can further comprise carboxymethylcellulose andstearic acid, in addition to water as a carrier. In certain embodiments,the combination of collagen containing the date palm extract whencomplexed with the carboxymethyl cellulose will be present in theinstant gel compositions in an amount of about 0.8 to about 2.0 wt. % byweight of the total gel composition, or about 0.8%, about 0.9%, about1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, or any range ofany two endpoints thereof, of this combination. Similarly, in certainembodiments, the stearic acid will be present in the instant gelcompositions in an amount of about 0.1 to about 0.3 μg, or about 0.1 μg,about 0.2 μg, about 0.3 μg, or any range of any two endpoints thereof,of stearic acid.

The present compositions can further comprise an anti-epileptic agent.In this regard, the present gel compositions can include about 0.1 toabout 2.5 wt. % of an anti-epileptic agent, or about 0.1%, about 0.2%,about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%,about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%,about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%,about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, or any rangeof any two endpoints thereof, of the anti-epileptic agent, on a wt. %basis with respect to 100 g of the gel compositions. In otherembodiments, the present gel compositions can includeabout 0.25 to about1.5 wt. % of the anti-epileptic agent, or about 0.75 wt. % of theanti-epileptic agent.

In certain embodiments, the anti-epileptic agent can be a phenobarbital.In further embodiments, the phenobarbital can be diazepam. Otheranti-epileptic agents, phenobarbitals, and the like are furthercontemplated for use herein. By way of non-limiting example, certainanti-epileptic agents that can be used in the present gel compositionscan include Brivaracetam (Briviact), Carbamazepine (Tegretol), Clobazam(Frisium), Clonazepam (Rivotril), Diazepam (Valium), Ethosuximide(Zarontin), Gabapentin (Neurontin), Lacosamide (Vimpat), Lamotrigine(Lamictal), Levetiracetam (Keppra), Midazolam, Oxcarbazepine(Trileptal), Perampanel (Fycompa), Phenobarbitone (Phenobarb), Phenytoin(Dilantin), Pregabalin (Lyrica), Primidone (Mysoline), Rufinamide(Inovelon), Sodium valproate (Epilim, Valpro), Tiagabine (Gabitril),Topiramate (Topamax), Vigabatrin (Sabril), and Zonisamide (Zonegran).

The present gel compositions may further includeone or more“pharmaceutically-acceptable excipients” or “pharmaceutically-acceptablecarriers” means a pharmaceutically acceptable material, composition, orvehicle involved in giving form or consistency to the gel composition.Each excipient or carrier must be compatible with the other ingredientsof the pharmaceutical composition when comingled such that interactionswhich would substantially reduce the efficacy of the active gelcompositions of this disclosure when administered to a subject andinteractions which would result in pharmaceutical compositions that arenot pharmaceutically acceptable are avoided. In addition, each excipientor carrier must of course be of sufficiently high purity to render itpharmaceutically-acceptable. Suitable pharmaceutically acceptableexcipients may include diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweeteners, flavoring agents, flavor masking agents, coloring agents,anticaking agents, humectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically-acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what otheringredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically-acceptable excipients inappropriate amounts for use in the gel-based formulations of thisdisclosure. In addition, there are resources available to the skilledartisan which describe pharmaceutically-acceptable excipients and may beuseful in selecting suitable excipients for use in the gel-basedcompositions of this disclosure. Examples include Remington'sPharmaceutical Sciences (Mack Publishing Company), The Handbook ofPharmaceutical Additives (Gower Publishing Limited), and The Handbook ofPharmaceutical Excipients (the American Pharmaceutical Association andthe Pharmaceutical Press), the contents of each of which may beincorporated herein in their entirety.

Therapeutic formulations comprising the gel compositions of thisdisclosure may be prepared for storage by mixing the gel compositionhaving the desired degree of purity with optional physiologicallyacceptable carriers, excipients or stabilizers (Remington'sPharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the formof aqueous solutions, lyophilized or other dried formulations.

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations may include semipermeable matrices ofsolid hydrophobic polymers containing the gel compositions of thisdisclosure in the form of shaped articles, e.g., films, ormicrocapsules. Examples of sustained-release matrices includepolyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate),or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919),copolymers of L-glutamic acid and .gamma. ethyl-L-glutamate,non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolicacid copolymers such as the LUPRON DEPOT™ (injectable microspherescomposed of lactic acid-glycolic acid copolymer and leuprolide acetate),and poly-D-(—)-3-hydroxybutyric acid. While polymers such asethylene-vinyl acetate and lactic acid-glycolic acid enable release ofmolecules for over 100 days.

Thus, one aspect of this disclosure is a therapeutic formulationcomprising the gel composition of this disclosure adapted for topicaladministration to a subject. Such topical formulations are particularlyuseful in the methods of treating, preventing, or alleviating a disease,disorder, or condition. The therapeutic formulation may comprise anappropriate dosage form for topical administration, such as a gel,cream, ointment, salve, or medicated bandage comprising the gelcompositions of this disclosure.

Another aspect of this disclosure is a therapeutic formulationcomprising the gel composition of this disclosure adapted for rectaladministration to a subject. Such rectal formulations are particularlyuseful in methods of treating, preventing, or alleviating inflammatorybowel diseases, e.g., colitis. The therapeutic formulation may comprisean appropriate dosage form for rectal administration, such as a gel,suspension, or solution comprising the gel compositions of thisdisclosure.

In further embodiments, the present subject matter relates to a methodfor treating a gastrointestinal inflammatory disorder, a bowel disease,disorder, or condition in a patient in need thereof, the methodcomprising topically administering a therapeutically effective amount ofa gel composition as described herein to a rectum of the patient. Inthis regard, the bowel disease, disorder, or condition treatable hereincan be selected from the group consisting of inflammatory bowel disease,ulcerative colitis, Crohn's disease, rectal complications, rectalwounds, diabetic ulcers, and any combination thereof. In one embodiment,the bowel disease, disorder, or condition is inflammatory bowel disease.In other embodiments, the bowel disease, disorder, or condition is agastrointestinal disorder.

Similar to the role of inflammation in slowing or preventing the healingof skin wounds, inflammatory bowel disease (IBD), specificallyulcerative colitis, is characterized by intestinal inflammation, andoxidative stress. Therefore, administration of the gel compositions ofthis disclosure to target oxidative stress can be used to treatinflammatory bowel diseases by reducing inflammation and oxidativestress in the intestinal mucosa.

The gel compositions of this disclosure may be administered orally orrectally on a chronic or intermittent basis and are suitable fortreating, reducing the risk of, preventing, or alleviating a symptom ofinflammatory bowel diseases, including ulcerative colitis, indeterminatecolitis, and Crohn's disease. In these methods, the response toadministration of the gel compositions of this disclosure may includeone or more of clinical response, mucosal healing, and remission.

To bring the gel compositions into contact with the inflamed intestinalmucosa, these gel compositions may be formulated for rectaladministration, as described above. In these methods, rectaladministration of a therapeutic formulation comprising the gelcomposition of this disclosure may be useful in treating, preventing, oralleviating inflammatory bowel diseases.

In certain embodiments, the topical administration of the gelcomposition herein provides a reduction in rectal bleeding of thepatient.

In further embodiments, the topical administration of the gelcomposition herein downregulates one or more rectal wound markersselected from the group consisting of VEGF, TNF-alpha, IL-1B, NFkB,STATS, COX2, and IL6.

In these therapeutic methods of this disclosure, the clinicianadministering treatment will be able to determine the appropriate dosefor the individual subject for weight-based or flat dosing (i.e., aparticular amount of the gel composition that is administered to everypatient regardless of weight). For the prevention or treatment ofdisease, the appropriate dosage of the gel compositions and any secondtherapeutic or other compound administered in combination with the gelcompositions may depend on the disease state being treated, e.g., thetype of wound to be treated or the gastrointestinal inflammatorydisorder to be treated (IBD, UC, CD) the severity and course of thedisease, whether the gel composition or combination is administered forpreventive or therapeutic purposes, previous therapy, the patient'sclinical history and response to the gel composition, and the discretionof the clinician. In these methods, the gel compositions can be suitablyadministered to the patient at one time or more typically over a seriesof treatments. For example, the gel compositions may be administeredonce every week, or once every two weeks, or once every four weeks, oronce every six weeks, or once every eight weeks for a period of onemonth (4 weeks), or two months, three months, or six months, or 12months, or 18 months, or 24 months, or chronically for the lifetime ofthe patient.

Alternatively, or additionally, the gel composition treatments may beself-administered by the patient. For repeated administrations overseveral days or longer, depending on the condition, the treatment can besustained until a desired suppression of disease symptoms occurs.However, other dosage regimens may be useful. Typically, the clinicianwill administer a gel composition of this disclosure (alone or incombination with a second compound) until a dosage(s) is reached thatprovides the required biological effect. The progress of the therapy iseasily monitored by conventional techniques and assays.

EXAMPLES Example 1 Preparation of Modified Collagen

A collagen hydrolysates solution was heated to 40-75° C., the pH wasadjusted to 5.0-6.5, and papain was added (−.01 to 0,1%) to performenzymolysis to obtain a first enzymolysis reaction solution.

Example 2 Collagen Characterization

Characterization of collagen used in situ in the present rectal gellingsystem was performed using a Tube inversion test. Two ml of the datepalm extract, vanillic acid, carboxymethyl cellulose, diazepam andstearic acid with the collagen hydrolysates in situ gelling system wastransferred into a 5 mL sample tube. The system pH was raised tophysiological pH by adding 20μL of 1 M NaOH followed by incubation at37° C. The hydrogel phase rheology was monitored by inverting the tubeat 2 min time interval after incubation. Separately, 2 ml of the gellingsystem was dialyzed against 1 Phosphate buffer saline pH 7.4 at 37 C for30 min. The system was monitored every 2 min to observe the gelation.

Example 3 Treatment

Collagen (5 to 15 mg/kg b.w), collagen enzymatic hydrolysate (25 to 80mg/kg b.w), date palm extract suspension (100 to 1000 mg/kg b.w) andvanillic acid (10 to 50 mg/kg b.w) were administered intra rectally fromday 6 to 15 into the lumen of the colon of DSS mice. Results of thesetreatments can be seen in FIGS. 1-5 .

Specifically, the present compositions provided higher clinicaleffectiveness in treatment of immunological mediated inflammatory boweldiseases of the intestinal-digestive tract, reduced disease symptoms andtreatment period. The clinical assessment on day 10 of rectal injuryusing dextran sulfate sodium/TNBS and acetic acid revealed that both themodified collagen 0.1 to 2% complexed with vanillic acid, date phenolsand chitosan demonstrated significant reduction in the rectal bleedingcompared to reference mesalamine treatment. The rectal wound markersVEGF, TNF-alpha, IL-1B and IL6 were downregulated in the injuredtissues. Collagen complex treatments showed significant reduction inmucosal damage score and facilitated faster regeneration of damagedmucosa.

It is to be understood that the gel composition is not limited to thespecific embodiments described above, but encompasses any and allembodiments within the scope of the generic language of the followingclaims enabled by the embodiments described herein, or otherwise shownin the drawings or described above in terms sufficient to enable one ofordinary skill in the art to make and use the claimed subject matter.

We claim:
 1. A method for treating a bowel disease, disorder, orcondition in a patient in need thereof, the method comprising: topicallyadministering a therapeutically effective amount of a gel composition toa rectum of the patient; the gel composition comprising: about 0.1 toabout 2.5 wt. % of an anti-epileptic agent; about 0.8 to about 2.0% wt.% of a collagen complexed with a date palm extract of Khalas cultivarand carboxymethylcellulose; including about 10 to about 50 μg/mL ofvanillic acid; about 0.1 to about 0.3 μg of stearic acid; and water;wherein all wt. % are based on g/100 g of the gel composition; whereinthe bowel disease, disorder, or condition is selected from the groupconsisting of rectal complications, rectal wounds, and a combinationthereof.
 2. The method of claim 1, wherein the topical administration ofthe gel composition provides a reduction in rectal bleeding of thepatient.
 3. The method of claim 1, wherein the topical administration ofthe gel composition downregulates one or more rectal wound markersselected from the group consisting of VEGF, TNF-alpha, IL-1B, NFkB,STATS, COX2, and IL6.
 4. The method of claim 1, the gel compositionfurther comprising one or more selected from the group consisting ofchitosan, timogen, propylene glycol, Carbopol, EDTA, and sodiumhydroxide.
 5. The method of claim 1, wherein the collagen is pepsintreated collagen I.
 6. The method of claim 1, wherein the collagenincludes collagen enzymatic hydrolysates.
 7. The method of claim 1,wherein the date palm extract includes phenolics in addition to vanillicacid.
 8. The method of claim 1, the gel composition further comprisingabout 0.25 to about 1.5 wt. % of the anti-epileptic agent.
 9. The methodof claim 1, the gel composition further comprising about 0.75 wt. % ofthe anti-epileptic agent.
 10. The method of claim 1, wherein theanti-epileptic agent is a phenobarbital.
 11. The method of claim 10,wherein the phenobarbital is diazepam.
 12. The method of claim 1,wherein the gel composition is formulated for topical administration.